Incomplete T-cell receptor-beta peptides target the mitochondrion and induce apoptosis.
The default pathway of cell-surface T-cell receptor (TCR) complex formation, and the subsequent transport to the membrane, is thought to entail endoplasmic reticulum (ER) localization followed by proteasome degradation of the unassembled chains. We show herein an alternative pathway: short, incomplete peptide versions of TCRbeta naturally occur in the thymus. Such peptides, which have minimally lost the leader sequence or have been massively truncated, leaving only the very C terminus intact, are sorted preferentially to the mitochondrion. As a consequence of the mitochondrial localization, apoptotic cell death is induced. Structure function analysis showed that both the specific localization and induction of apoptosis depend on the transmembrane domain (TMD) and associated residues at the COOH-terminus of TCR. Truncated forms of TCR, such as the short peptides that we detected in the thymus, may be products of protein degradation within thymocytes. Alternatively, they may occur through the translation of truncated mRNAs resulting from unfruitful rearrangement or from germline transcription. It is proposed that mitochondria serve as a subcellular sequestration site for incomplete TCR molecules.
Shani
Nir
N
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
Rubin-Lifshitz
Hila
H
Peretz-Cohen
Yifat
Y
Shkolnik
Ketty
K
Shinder
Vera
V
Cohen-Sfady
Michal
M
Shav-Tal
Yaron
Y
Barda-Saad
Mira
M
Zipori
Dov
D
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D019556:COS Cells; D002470:Cell Survival / Q000276:immunology; D002522:Chlorocebus aethiops; D015329:Gene Rearrangement, T-Lymphocyte; D049452:Green Fluorescent Proteins / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008928:Mitochondria / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000276:immunology*; D012333:RNA, Messenger / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology
D007135:Immunoglobulin Variable Region; D012333:RNA, Messenger; D016693:Receptors, Antigen, T-Cell, alpha-beta; D049452:Green Fluorescent Proteins